In general, polyethylene (mainly ultrahigh molecular weight polyethylene, hereinafter referred to as PE) has been conventionally used as a component member of artificial joints, such as an artificial hip joint and an artificial knee joint. However, when the artificial joint was used in vivo, there was a tendency that lysis of bone (i.e. osteolysis) had been induced by the wear debris of PE which was produced through a frictional movement. When the osteolysis happened, so-called loosening in which the fixing force of an artificial joint and a bone becomes weaker arose, and the loosening had become a big problem as complication of an arthroplasty. Usual abrasion loss of the above-mentioned PE was about 0.1 to 0.2 mm per year, and there was no problem for a certain period of time (for example, for about several years) after the arthroplasty. However, the amount of the above-mentioned loosening became remarkable after a lapse of about five years, and thus a re-operation of exchanging the artificial joint should be needed, and that could impose a heavy burden on the patients.
In the artificial hip joint, the size of a femoral head component has been enlarged for the purpose of improving the range of motion and of prevention of dislocation. Since there is a limit for the size of a cup to be housed in an acetabulum, thinning of (the thickness of) the acetabular cup made of PE has been required corresponding to the enlarging the size of the femoral head component. There was a limit in advancing the thinning of the acetabular cup due to the viewpoints of the properties of wear resistance, deformation resistance and fracture resistance.
One of the solutions for the loosening is to decrease the amount of the wear debris of PE, and to this end extensive researches on crosslinked PE wherein molecular chains are crosslinked thereamong (hereinafter referred to as CLPE) by irradiating PE with an electron beam or a gamma ray have been carried out in recent years (Patent Documents 1 to 3). These researches utilize the matter that irradiating a polymer material with a radiation having high energy such as an electron beam or a gamma ray generates free radicals due to cutoff of molecular chains, followed by occurring the recombination or crosslinking reaction of the molecular chains. The above-mentioned CLPE is excellent in the property of wear resistance compared with the conventional PE, so that it is reported that the amount of the abrasion loss can be reduced even to the order of about one fifth to one tenth of the conventional amount.
On the other hand, intensive researches of alternate material of PE to be used for an artificial joint have also been carried out, thereby polyetheretherketone (hereinafter referred to as PEEK) is taken as an example thereof, which is an engineering plastic excellent in the properties of deformation resistance and fracture resistance. Although the property of wear resistance of PEEK itself is not so sufficient, the property is intended to be improved by compositing PEEK with a carbon fiber. However, use of rigid carbon fiber may damage the femoral head component to be combined therewith, and thus a PEEK material having sufficient properties for the artificial joints has not been obtained.
Alternatively, it has also been studied to improve the property of slidability of the surface of the sliding portion by forming a coating layer on the surface of PE. For example, it is known a method of fixing a coating layer of a random copolymer comprising an allylamine and a group analogous to a phosphorylcholine group to the surface of a medical appliance, which is required to have an excellent sliding property such as an artificial joint, thereby providing a biocompatibility and a surface lubricity thereto (Patent Document 4).
Particularly, an artificial joint component made from a polymeric material which is excellent in reducing the abrasion of the artificial joint and is capable of suppressing the generation of wear debris than ever before can be obtained by grafting a polymerizable monomer having a phosphoryl choline group onto the slidable surface of the artificial joint made from PE (Patent Document 5).
In the conventional photo-graft polymerization method, a photopolymerization initiator, for example, benzophenone (BP) was used. A “grafting from” method, wherein the surface of the substrate is used as the starting point of graft polymerization, is advantageous in achieving high densification of the graft layer compared with the other techniques, and it is necessary to preliminarily apply the polymerization initiator to the surface of the substrate which should be treated in order to realize this method. Patent Document 5 discloses an invention to use CLPE as a substrate, 2-methacryloyloxyethyl phosphorylcholine (MPC) as a monomer and BP as a photopolymerization initiator, thereby causing MPC graft polymerization on the surface of the substrate to form a membrane of a layer or MPC on the surface thereof.
The MPC polymer produced by the method of Patent Document 5 is useful as the material for forming an ideal biocompatible surface. However, in the case where the product therefrom is used as a biocompatible material, it is desirable that no photopolymerization initiator remains on the surface of the substrate and in the graft polymer layer after performing the graft polymerization reaction. Therefore, according to the method of Patent Document 5, there was another problem that the radical initiator remaining after performing the graft polymerization reaction should be removed from the surface of the substrate and the graft polymer layer.
It is reported that there are the methods of generating radicals using high-energy radiations, for example, a gamma ray, an electron beam (beta ray), an ionic beam, an X-ray and so on as the methods of performing the graft polymerization without using the polymerization initiator (Patent Document 6).
On the other hand, metal materials used for the medical appliance (for example, an artificial kidney, an artificial lung, an artificial trachea, and a blood pump for an (auxiliary) artificial heart, an artificial valve, an artificial blood vessel, a catheter, a cardiac pacemaker, an artificial bone, an artificial tendon, an artificial knuckle and a bone securing plate, a bone screw and so on) almost satisfies the condition of the mechanical properties, but they are not always sufficient to the biocompatibility (including the hemocompatibility). For example, when blood components produce thrombus by contacting with the surface of the medical appliance, they could inhibit the blood flow and thereby could seriously harm the human body. Therefore, an agent which suppresses the protective response of the body is required in therapeutic interventions using the medical appliance in clinical practice. Side effects caused by prolonged use of the above-mentioned agent are serious problems. For example, side effects caused by frequent use of anticoagulant agents include internal bleeding in the skin, nose bleeding, bleeding from the gums, excessive bleeding from the wound, bleeding such as hypermenorrhea, bloody sputum, hematuria, hematochezia as well as dizziness and wobble. Particularly, bleedings such as gastrointestinal bleeding, intracranial bleeding and intraperitoneal bleeding may place the patient's life in peril when finding of such bleedings would be delayed. For the developments of the medical appliance which can be embedded in a living body and used therein for a long period of time, a material having the biocompatibility (including the hemocompatibility) is essential.
In the present medical practice, a method to use a biologically active substance capable of inhibiting thrombus formation is used so as to impart antithrombotic properties to a surface of a medical device, for example, an artificial organ. To this end, there is a method of fixing a biologically active substance such as urokinase having a function of dissolving thrombus thus formed, heparin capable of inhibiting a function of thrombin as a coagulation factor, or prostaglandin as a platelet activation inhibitor to a surface of a material. However, the side effects caused by these agents can not be disregarded and is a big problem. In addition, it is extremely difficult to control the releasing rate of the agent and the effects therefrom cannot be expected after release of the agents. Most of the drug eluting type medical appliance (particularly stent) use a non-biodegradable polymers including, for example, poly(n-butyl methacrylate), poly(dimethyl siloxane) and so on. Thus, it is reported that polymers which remain on the surface of the stent after the drug eluted may cause an inflammatory reaction and/or a thrombus formation, and also cause a problem of failing to endothelize on the surface of the stent.
In order to impart antithrombotic properties to the surfaces of the medical appliance, for example, the artificial organ, a method utilizing a biological reaction is employed. That is, it is a method in which coagulation factors and platelets are moderately aggregated to a surface of a material to form a thrombus membrane, and endothelial cells constituting a vascular wall are engrafted on the thrombogenic membrane as a footing and a thin neointima is formed on the surface of the material by further growth of the endothelial cells. However, there is a possibility that a thrombus may occur during the period of about one month after an operation until endothelial cells will cover a medical appliance. Then, it became necessary to administer an antiplatelet drug and thus the side effect caused by the drug cannot be neglected.
Furthermore, there is also employed a method in which antithrombotic properties are obtained by surface properties of the material per se without using a biologically active substance or a drug. By the way, thrombus formation occurs due to an adsorption of a plasma protein and a subsequent activation of platelets, and the adsorption of the plasma protein onto the surface of the material physicochemically proceeds. Then, in order to prevent formation of thrombus, it is important to make the interaction between the material and blood as little as possible. Thus, it is desirable to convert the surface of the material into the state almost as close to blood as possible by reforming the surface thereof in order to decrease the above interaction.
Such a reforming method includes, for example, a method in which a water-soluble polymer is bonded by a coupling reaction utilizing functional groups such as hydroxyl and amino groups of the surface of the material.
For example, a method of fixing a random copolymer which consists of an allylamine and a group analogous to a phosphorylcholine group for a medical material is disclosed (Patent Document 7). When the copolymer is used as in the above method, the content of the phosphorylcholine group on the surface of the medical material decreases, thereby causing a problem that each of the biocompatibility (including the hemocompatibility), the hydrophilicity and the surface lubricity could not be attained to a satisfactory extent. On the other hand, when the content of the phosphorylcholine group in the copolymer is excessive, there arises another problem that the copolymer becomes soluble in water and adhesion thereof would not be maintained when used for a long period of time. Actually, it is reported that, in an artificial heart which was coated with an MPC copolymer, merely 5% of MPC copolymer remained after use thereof for ninety-one days (Non-Patent Document 1).
Another reforming method includes a method in which peroxide as a polymerization initiator is produced on a surface of a material by irradiating with ultraviolet rays, electric beams or ion beams in the presence of oxygen, and then a water-soluble vinyl monomer is subjected to radical polymerization to form a water-soluble polymer chain on the surface of the material. It is reported that this water-soluble polymer chain prevents a protein from being directly contacted with the surface of the material and inhibits the adsorption of the protein onto the surface of the material.
For example, it is reported that anti-protein adsorption property can be improved by grafting MPC as a monomer on a polyethylene surface through irradiation with ultraviolet rays (Patent Document 8). According to the method of Patent Document 2, it is designed to improve the wear resistant property of a substrate through imparting the surface of the substrate with highly slidability by causing graft polymerization of MPC onto PE using PE without ketone group as the substrate, MPC as a reactive monomer and BP as a photopolymerization initiator.
Taking a dental implant into account, there has conventionally been carried out a prosthetic treatment with retrievable partial denture or bridge denture for repairing a loss of teeth due to periodontal diseases and dental caries. However, retrievable partial denture has an aesthetic problem attributed from a metal hook and a problem of providing a feeling of resistance to implementation, while bridge denture has a problem that burden for abutment tooth to be ground cannot be avoided. A dental implant treatment has attracted special interest recently as a prosthetic treatment and is one of selection choices, and the number of cases has remarkably increased. In loss of teeth due to fracture of an alveolar bone, teeth are lost together with the alveolar bone around teeth and thus bone width and bone height enough to carry out embedding of implant were not often obtained. However, it has become possible to apply a bone grafting method, a guided bone regeneration (GBR) method, a bone lengthening method, a bone prosthetic material, and a bone augmentation method utilizing cytokines, thus increasing the number of cases of application of a dental implant. In some cases, it becomes possible to impart an occlusion function through embedding due to one-stage implant and mounting of an upper structure at an initial stage after embedding, by improving surface properties of an implant or controlling a load on an implant body after embedding. Establishment of a method of early and surely acquiring oseointegration remarkably contributes to stabilization of the occlusion function of the dental implant. However, even if oseointegration is acquired, it is impossible to persistently avoid the circumstance in which the implant body as foreign matters penetrates through the epithelium. Therefore, how plaque deposition in this gingival penetration portion is inhibited and inflammation around the implant body is prevented, was an important object for enabling the dental implant to function over a long period. Particularly in two-stage implant, the micro-gap existing between the abutment and the fixture bonding portion makes it easy to cause inflammation around the implant. Also, local bone resorption temporarily occurs due to a removal of the bond formed on so-called healing cap or the top portion of the implant body during secondary surgery, and thus down growth of gingival epithelia is likely to occur, thus leading to the situation where plaque deposition is likely to occur, and which situation becomes similar to periodontal diseases, thereby being obliged to remove the dental implant in some situations, which could arise a clinical problem.    Patent Document 1: Japanese Patent No. 2984203    Patent Document 2: U.S. Pat. No. 6,228,900    Patent Document 3: International Publication No. WO97/29793    Patent Document 4: International Publication No. WO01/05855    Patent Document 5: Japanese Unexamined Patent Publication (Kokai) No. 2003-310649    Patent Document 6: Japanese Unexamined Patent Publication (Kokai) No. 2008-53041    Patent Document 7: International Publication No. WO01/05855    Patent Document 8: Japanese Unexamined Patent Publication (Kokai) No. 2007-202965    Nonpatent Document 1: In Vivo Evaluation of a MPC Polymer Coated Continuous Flow Left Ventricular Assist System, ARTIFICIAL ORGANS, VOL 27, No. 2, 2003